Knowledge of the mechanisms underlying the normal development of blood cells is important in understanding and developing new treatments for various blood diseases, including leukemias. The long range goals of this project are to further our understanding of the mechanisms involved in leukemia by understanding the effects of various leukemia oncogenes on the transcription factors which regulate normal myeloid development from stem cells. Previous work in our laboratory has led to the identification of the transcription factor CCAAT Enhancer Binding Protein a (C/EBPa) as being absolutely critical for differentiation of normal myeloid blasts, and identified abnormalities in C/EBPa as playing a critical role in a number of specific types of Acute Myeloid Leukemia (AML), as noted in the Progress Report. Over the next 5 years, we propose to extend the study of how oncogenes affect this critical transcription factor in cell differentiation. We therefore propose the following Specific Aims: (1) To test the hypothesis that the interaction between PML/RAR and C/EBPa is responsible for the differentiation block in Acute Promyelocytic Leukemia (APL); (2) To understand the role of C/EBPb in the pathogenesis of APL? (Years 1-5); and (3) To investigate the synergism between loss of function of C/EBPa and leukemia oncogenes.